5,5-diphenyl barbituric acid (DPB) is a member of the non-sedating barbiturates and a metabolite of 1,3-dimethoxymethyl-5,5-diphenyl-barbituric acid (DMMDPB) and monomethoxymethyl-5,5-diphenylbarbituric acid (MMMDPB). Since DPB synthesis was first reported in 1935, the therapeutic use of 5,5-diphenyl barbituric acid (DPB) was overlooked, in part because of its lack in purported hypnotic activities. (McElvain et al. “5,5-Diphenylbarbituric Acid” J. Am. Chem. Soc. 1935, 57:1301-04). DPB was found to be effective only in exceedingly large doses and therefore no pharmacological application was suggested. DPB has the following structure, and it exists as a free acid form. To the best of the inventors' knowledge, no salt forms of DPB have been isolated and reported.

In 1945, Merritt et al. reported among hundreds of screened compounds DPB for its elevation of the electroshock seizure thresholds in cats. (“Experimental determination of anticonvulsive activity of chemical compounds” Epilepsia, 1945, 3: 751-75). Merritt et al. described DPB as a weak anticonvulsant. DPB (free acid form) was given orally in capsules but the authors pointed out that “some compounds were effective when given in solution but totally ineffective when given in capsules.” In 1947, Alles et al. found that DPB (free acid form) has activity in prolonging the duration of an electric current required to produce a seizure in rabbits (“Comparative central depressant actions of some 5-phenyl-5-alkyl-barbituric acids” J. Pharmacol., 1947, 89: 356-367).
In 1973, Raines et al. re-evaluated the anticonvulsant effects of DPB in a mouse model using the maximal electroshock seizure (MES) test. (“A comparison of the anticonvulsant, neurotoxic and lethal effects of diphenylbarbituric acid, phenobarbital and dipheylhydantoin in the mouse” Journal of Pharmacology 1973, 186: 315-322). DPB, given by stomach tube, was effective in protecting mice from seizure induced either by electroshock or pentylenetetrazole (a chemical convulsant). However, it was not possible to give enough DPB via stomach tube to produce neurotoxicity or death, as the poorly soluble DPB (free acid form) could not be adequately absorbed to achieve these latter end-points. In subsequent rat studies, Raines et al. monitored plasma and brain concentrations of DPB and speculated that DPB (free acid form) is probably slowly absorbed from the gastrointestinal tract and slowly moves into the brain to provide an anti-seizure activity. (“The effects of 5,5-diphenyl-barbituric acid on experimental seizures in rats: correlation between plasma and brain concentrations and anticonvulsant activity” Epilepsia, 1975, 16:575-581).
DPB is not a viable oral therapeutic agent, in large part because of the problems associated with its poor bioavailability. Water solubility of DPB is known to be exceedingly poor, 1/100 fold less soluble as compared to phenobarbital in aqueous solution at pH 7. (See, Epilepsia, 1973, 186, 315-22). DPB free acid has been administered orally as an insoluble form (i.e., suspension). Indeed, Raines et al. stated “[b]ecause of the limited aqueous solubility, gastrointestinal absorption was not efficient . . . .” J. Pharmacol. & Exp. Ther. 1973, 186: 315. Hence, the low oral absorption of DPB contributes to its sub-optimal bioavailability and so far has limited the use of DPB as an oral therapeutic agent. Several studies point to the conclusion that oral dosage of DPB (free acid form) is ineffective. Prior art does not suggest a salt form of any non-sedating barbiturates that may improve bioavailability. Specifically it is known that with some barbiturates (e.g., pentobarbital), the sodium salts are absorbed more rapidly than the corresponding free acids, but not its bioavailability. (The Pharmacological Basis of Therapeutics 2001, p. 417, Tenth Ed.) Because DPB in its free acid form was found to be effective only in large doses, no pharmacological application of DPB has been suggested.
Despite substantial effort, there has been no success in improving the bioavailability of DPB. This includes exploring alternative routes of administration. To this end, Raines et al. compared the intraperitoneal and oral administrations of DPB (free acid form) and correlated the plasma DPB concentrations with the anticonvulsant activity. (“The effects of 5,5-diphenyl barbituric acid on experimental seizures in rats: correlation between plasma and brain concentrations and anticonvulsant activity” Epilepsia, 1975, 16, 575-81). It was found that oral gavage of DPB (free acid form) is considerably less potent when compared to intraperitoneal administration of DPB, which correlates well with the observation that oral absorption for DPB is poor. Despite a better bioavailability, intraperitoneal administration does not represent a practical therapeutic route.
To circumvent the low absorption problems associated with DPB, Raines et al. examined the preparation of a DPB saline solution for intravenous administration. (Epilepsia, 1985, 26: 158-166). Sodium hydroxide is required to keep DPB in solution, resulting in a high pH of about 10.5 to about 12 for the solution. Intravenous administration or oral administration of such an alkaline solution would cause significant tissue necrosis, and thus does not represent a feasible choice for safe patient use. Other than the known intravenous and intraperitoneal administrations of DPB (free acid forms), there is no other known dosage form of DPB that would provide good bioavailability in a mammal and hence permit optimal and sustained circulating levels of DPB.
Several attempts have been made to provide higher levels of DPB, including administration of prodrugs. In humans, DMMDPB was found to be better absorbed and have a longer half-life as compared to rats or dogs (See, e.g., WO 02/07729). The unexpectedly high absorption and prolonged half-life in humans creates the possibility that DMMDPB may result in a sustained source of DPB that provides extended periods of anticonvulsant efficacy. To this end, several efforts have been made to use DMMDPB and MMMDPB as prodrugs in attempt to provide blood levels of DPB to treat neurological diseases. For example, U.S. Pat. No. 6,756,379 discloses the use of DMMDPB and MMMDPB against neurological conditions including, inter alia, cerebral ischemia, head trauma, stroke, and epilepsy. WO 2004/052350 describes the use of DMMDPB, and MMMDPB against movement disorders; more specifically, essential tremor. The use of DMMDPB and MMMDPB as a prodrug for DPB has required larger doses of prodrug (because of poor bioavailability) to provide an optimal, steady blood level of DPB. Inter- and intra-individual variability was seen in serum DPB levels when DMMDPB was orally administered. The inter-individual variability may reflect poor and variable bioavailability or may be attributable to the differences in the metabolism of DMMDPB to MMMDPB and DPB by liver enzymes whose activity may varies with patients and their health status. Poor bioavailability may lead to intra- and inter-individual variability. Variable serum levels are not desirable because it may increase the incidence of break-through seizures and adverse effects produced by excessive drug levels.
There is a continuing need to provide a composition and a method for improved bioavailability of DPB and enhancing brain delivery of the same to the central nervous system in mammals. There is no prior art disclosing an oral solid dosage form of DPB in its salt forms that exhibits an improved bioavailability. We report herein a reliable synthesis of salt forms of DPB and production of an oral solid dosage form of a DPB salt. Surprisingly, an oral dosage of DPB salts, in contrast to its free acid counterpart, provides a high and sustained blood level of DPB and enhances brain delivery of DPB so that it can exert its effects in the central nervous system. An improved bioavailability of DPB is believed to contribute to its beneficial effects in the treatment of neurological conditions.